High-altitude illnesses (HAIs) result from acute exposure to high altitude/hypoxia. Numerous molecular mechanisms affect appropriate acclimatization to hypobaric and/or normobaric hypoxia and curtail ...the development of HAIs. The understanding of these mechanisms is essential to optimize hypoxic acclimatization for efficient prophylaxis and treatment of HAIs. This review aims to link outcomes of molecular mechanisms to either adverse effects of acute high-altitude/hypoxia exposure or the developing tolerance with acclimatization. After summarizing systemic physiological responses to acute high-altitude exposure, the associated acclimatization, and the epidemiology and pathophysiology of various HAIs, the article focuses on molecular adjustments and maladjustments during acute exposure and acclimatization to high altitude/hypoxia. Pivotal modifying mechanisms include molecular responses orchestrated by transcription factors, most notably hypoxia inducible factors, and reciprocal effects on mitochondrial functions and REDOX homeostasis. In addition, discussed are genetic factors and the resultant proteomic profiles determining these hypoxia-modifying mechanisms culminating in successful high-altitude acclimatization. Lastly, the article discusses practical considerations related to the molecular aspects of acclimatization and altitude training strategies.
Millions of people worldwide visit, live or work in the hypoxic environment encountered at high altitudes and it is important to understand the biomolecular responses to this stress. This would help ...design mitigation strategies for high altitude illnesses. In spite of a number of studies spanning over 100 years, still the complex mechanisms controlling acclimatization to hypoxia remain largely unknown. To identify potential diagnostic, therapeutic and predictive markers for HA stress, it is important to comprehensively compare and analyse these studies. Towards this goal, HighAltitudeOmicsDB is a unique resource that provides a comprehensive, curated, user-friendly and detailed compilation of various genes/proteins which have been experimentally validated to be associated with various HA conditions, their protein-protein interactions (PPIs) and gene ontology (GO) semantic similarities. For each database entry, HighAltitudeOmicsDB additionally stores the level of regulation (up/down-regulation), fold change, study control group, duration and altitude of exposure, tissue of expression, source organism, level of hypoxia, method of experimental validation, place/country of study, ethnicity, geographical location etc. The database also collates information on disease and drug association, tissue-specific expression level, GO and KEGG pathway associations. The web resource is a unique server platform that offers interactive PPI networks and GO semantic similarity matrices among the interactors.These unique features help to offer mechanistic insights into the disease pathology. Hence, HighAltitudeOmicsDBis a unique platform for researchers working in this area to explore, fetch, compare and analyse HA-associated genes/proteins, their PPI networks, and GO semantic similarities. The database is available at http://www.altitudeomicsdb.in .
•D4F was administered at 10 mg/kg BW for 7 days (i.p.) prior to hypoxia exposure.•D4F prophylaxis strengthened redox and energy homeostasis during hypoxia.•D4F prophylaxis also subdued ...hypoxia-induced inflammation.•The positive effects of D4F on lipid metabolism were partially reversed in normoxia.
Apo-A1 is correlated with conditions like hyperlipidemia, cardiovascular diseases, high altitude pulmonary edema and etc. where hypoxia constitutes an important facet.Hypoxia causes oxidative stress, vaso-destructive and inflammatory outcomes.Apo-A1 is reported to have vasoprotective, anti-oxidative, anti-apoptotic, and anti-inflammatory effects. However, effects of Apo-A1 augmentation during hypoxia exposure are unknown.In this study, we investigated the effects of exogenously supplementing Apo-A1-mimetic peptide on SD rats during hypoxia exposure. For easing the processes of delivery, absorption and bio-availability, Apo-A1 mimetic peptide D4F was used. The rats were given 10 mg/kg BW dose (i.p.) of D4F for 7 days and then exposed to hypoxia. D4F was observed to attenuate both oxidative stress and inflammation during hypoxic exposure. D4F improved energy homeostasis during hypoxic exposure. D4F did not affect HIF-1a levels during hypoxia but increased MnSOD levels while decreasing CRP and Apo-B levels. D4F showed promise as a prophylactic against hypoxia exposure.
Abstract
High altitude acclimatization and disease have been the centerpiece of investigations concerning human health at high altitude. Almost all investigations have focused on either understanding ...and ameliorating high altitude disease or finding better methods of acclimatization/training at high altitude. The aspect of altitude de-induction/de-acclimatization has remained clouded despite the fact that it was documented since the first decade of twentieth century. A few recent studies, particularly in China, have stated unanimously that high altitude de-acclimatization involved multiple observable clinical symptoms ranging from headache to abdominal distention. These symptoms have been collectively referred to as “high altitude de-acclimatization syndrome” (HADAS). However, computational omics and network biology centric investigations concerning HADAS are nascent. In this study, we focus on the quantitative proteo-informatics, especially network biology, of human plasma proteome in individuals who successfully descended from high altitude areas after a stay of 120 days. In brief, the protein list was uploaded into STRING and IPA to compute z-score based cut-offs which were used to analyze the directionality and significance of various identified protein networks as well as the proteins within them. Relevant upstream regulators extracted using computational strategies were also validated. Time-points till the 180th day of de-induction have been investigated to comparatively assess the changes in the plasma proteome and protein pathways of such individuals since the 7th day of arrival at altitude. Our investigation revealed extensive effects of de-induction on lipid metabolism, inflammation and innate immune system as well as coagulation system. This novel study provides a conceptual framework for formulating therapeutic strategies to ease the symptoms of HADAS during de-acclimatization. Such strategies should focus on normalization of lipid metabolism, inflammatory signaling and coagulation systems.
Oxygen-compromised environments, such as high altitude, air travel, and sports, and pathological conditions, such as solid tumors, have been suggested to be prothrombotic. Despite the indispensable ...role of platelets in thrombus formation, the studies linking hypoxia, platelet reactivity, and thrombus formation are limited. In the present study, platelet proteome/reactivity was analyzed to elucidate the acute hypoxia-induced prothrombotic phenotype. Rats exposed to acute simulated hypoxia (282 torr/8% oxygen) demonstrated a decreased bleeding propensity and increased platelet reactivity. Proteomic analysis of hypoxic platelets revealed 27 differentially expressed proteins, including those involved in coagulation. Among these proteins, calpain small subunit 1, a 28-kDa regulatory component for calpain function, was significantly upregulated under hypoxic conditions. Moreover, intraplatelet Ca2+ level and platelet calpain activity were also found to be in accordance with calpain small subunit 1 expression. The inhibition of calpain activity demonstrated reversal of hypoxia-induced platelet hyperreactivity. The prothrombotic role for calpain was further confirmed by an in vivo model of hypoxia-induced thrombosis. Interestingly, patients who developed thrombosis while at extreme altitude had elevated plasma calpain activities and increased soluble P-selectin level. In summary, this study suggests that augmented calpain activity is associated with increased incidence of thrombosis under hypoxic environments.
•Hypoxia induces altered platelet proteome/reactivity, which correlates with a prothrombotic phenotype.•CAPNS1-dependent calpain activity in platelet activation cascade is associated with hypoxia-induced thrombogenesis.
Hypobaric hypoxia elicits several patho-physiological manifestations, some of which are known to be lethal. Among various molecular mechanisms proposed so far, perturbation in redox state due to ...imbalance between radical generation and antioxidant defence is promising. These molecular events are also related to hypoxic status of cancer cells and therefore its understanding has extended clinical advantage beyond high altitude hypoxia. In present study, however, the focus was to understand and propose a model for rapid acclimatization of high altitude visitors to enhance their performance based on molecular changes. We considered using simulated hypobaric hypoxia at some established thresholds of high altitude stratification based on known physiological effects. Previous studies have focused on the temporal aspect while overlooking the effects of varying pO2 levels during exposure to hypobaric hypoxia. The pO2 levels, indicative of altitude, are crucial to redox homeostasis and can be the limiting factor during acclimatization to hypobaric hypoxia. In this study we present the effects of acute (24h) exposure to high (3049m; pO2: 71kPa), very high (4573m; pO2: 59kPa) and extreme altitude (7620m; pO2: 40kPa) zones on lung and plasma using semi-quantitative redox specific transcripts and quantitative proteo-bioinformatics workflow in conjunction with redox stress assays. It was observed that direct exposure to extreme altitude caused 100% mortality, which turned into high survival rate after pre-exposure to 59kPa, for which molecular explanation were also found. The pO2 of 59kPa (very high altitude zone) elicits systemic energy and redox homeostatic processes by modulating the STAT3-RXR-Nrf2 trio. Finally we posit the various processes downstream of STAT3-RXR-Nrf2 and the plasma proteins that can be used to ascertain the redox status of an individual.
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•A comparison of effects on redox and energy homeostasis between three altitude zones.•Exposure at 59kPa (10h) followed by normoxia (1h) rescues homeostasis at 40kPa.•Redox and energy homeostasis dependent on STAT-3-RXR-Nrf interplay.•Lung redox and energy homeostasis fails at 15,000ft.•Systemic redox and energy homeostasis activated on failure of lung homeostatic mechanisms.
Human Acclimatization and therapeutic approaches are the core components for conquering the physiological variations at high altitude (≥2500 m) exposure. The declined atmospheric pressure and reduced ...partial pressure of oxygen at high altitudes tend to decrease the temperature by several folds. Hypobaric hypoxia is a major threat to humanity at high altitudes, and its potential effects include altitude mountain sickness. On severity, it may lead to the development of conditions like high-altitude cerebral edema (HACE) or high-altitude pulmonary edema (HAPE) and cause unexpected physiological changes in the healthy population of travelers, athletes, soldiers, and low landers while sojourning at high altitude. Previous investigations have been done on long-drawn-out acclimatization strategies such as the staging method to prevent the damage caused by high-altitude hypobaric Hypoxia. Inherent Limitations of this strategy hamper the daily lifestyle and time consuming for people. It is not suitable for the rapid mobilization of people at high altitudes. There is a need to recalibrate acclimatization strategies for improving health protection and adapting to the environmental variations at high altitudes. This narrative review details the geographical changes and physiological changes at high altitudes and presents a framework of acclimatization, pre-acclimatization, and pharmacological aspects of high-altitude survival to enhance the government efficacy and capacity for the strategic planning of acclimatization, use of therapeutics, and safe de-induction from high altitude for minimizing the life loss. It's simply too ambitious for the importance of the present review to reduce life loss, and it can be proved as the most essential aspect of the preparatory phase of high-altitude acclimatization in plateau regions without hampering the daily lifestyle. The application of pre-acclimatization techniques can be a boon for people serving at high altitudes, and it can be a short bridge for the rapid translocation of people at high altitudes by minimizing the acclimatization time.
Adaptation to hypobaric hypoxia is required by animals and human in several physiological and pathological situations. Hypobaric hypoxia is a pathophysiological condition triggering redox status ...disturbances of cell organization leading, via oxidative stress, to proteins, lipids, and DNA damage. Identifying the molecular variables playing key roles in this process would be of paramount importance to shed light on the mechanisms known to counteract the negative effects of oxygen lack. To obtain a molecular signature, changes in the plasma proteome were studied by using proteomic approach. To enrich the low-abundance proteins in human plasma, two highly abundant proteins, albumin and IgG, were first removed. By comparing the plasma proteins of high altitude natives with those of a normal control group, several proteins with a significant alteration were found. The up-regulated proteins were identified as vitamin D-binding protein, hemopexin, alpha-1-antitrypsin, haptoglobin β-chain, apolipoprotein A1, transthyretin and hemoglobin beta chain. The down-regulated proteins were transferrin, complement C3, serum amyloid, complement component 4A and plasma retinol binding protein. Among these proteins, the alterations of transthyretin and transferrin were further confirmed by ELISA and Western blotting analysis. Since all the up- and down- regulated proteins identified above are well-known inflammation inhibitors and play a positive anti-inflammatory role, these results show that there is some adaptive mechanism that sustains the inflammation balance in high altitude natives exposed to hypobaric hypoxia.
Hypobaric hypoxia causes complex changes in the expression of genes, including stress related genes and corresponding proteins that are necessary to maintain homeostasis. Whereas most prior studies ...focused on single proteins, newer methods allowing the simultaneous study of many proteins could lead to a better understanding of complex and dynamic changes that occur during the hypobaric hypoxia.
In this study we investigated the temporal plasma protein alterations of rat induced by hypobaric hypoxia at a simulated altitude of 7620 m (25,000 ft, 282 mm Hg) in a hypobaric chamber. Total plasma proteins collected at different time points (0, 6, 12 and 24 h), separated by two-dimensional electrophoresis (2-DE) and identified using matrix assisted laser desorption ionization time of flight (MALDI-TOF/TOF). Biological processes that were enriched in the plasma proteins during hypobaric hypoxia were identified using Gene Ontology (GO) analysis. According to their properties and obvious alterations during hypobaric hypoxia, changes of plasma concentrations of Ttr, Prdx-2, Gpx -3, Apo A-I, Hp, Apo-E, Fetub and Nme were selected to be validated by Western blot analysis.
Bioinformatics analysis of 25 differentially expressed proteins showed that 23 had corresponding candidates in the database. The expression patterns of the eight selected proteins observed by Western blot were in agreement with 2-DE results, thus confirming the reliability of the proteomic analysis. Most of the proteins identified are related to cellular defense mechanisms involving anti-inflammatory and antioxidant activity. Their presence reflects the consequence of serial cascades initiated by hypobaric hypoxia.
This study provides information about the plasma proteome changes induced in response to hypobaric hypoxia and thus identification of the candidate proteins which can act as novel biomarkers.
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